tbuckley/cabot-search huggingface dataset:
Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling
Authors: Tamina Rückert, Geoffroy Andrieux, Melanie Boerries, Kathrin Hanke-Müller, Nadine M. Woessner, Stephanie Doetsch, Christoph Schell, Konrad Aumann, Julia Kolter, Annette Schmitt-Graeff, Marcel Schiff, Lukas M. Braun, Eileen Haring, Sandra Kissel, Benjamin A. Siranosian, Ami S. Bhatt, Peter Nordkild, Jan Wehkamp, Benjamin A. H. Jensen, Susana Minguet, Justus Duyster, Robert Zeiser, Natalie Köhler
Journal: Science Translational Medicine (2022)

Acute graft-versus-host disease (aGVHD), which is driven by allogeneic T cells, has a high mortality rate and limited treatment options. Human β-defensin 2 (hBD-2) is an endogenous epithelial cell–derived host-defense peptide. In addition to its antimicrobial effects, hBD-2 has immunomodulatory functions thought to be mediated by CCR2 and CCR6 in myeloid cells. In this study, we analyzed the effect of recombinant hBD-2 on aGVHD development. We found that intestinal β-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal β-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency.
Arithmetic value representation for hierarchical behavior composition
Authors: Hiroshi Makino
Journal: Nature Neuroscience (2022)

Abstract The ability to compose new skills from a preacquired behavior repertoire is a hallmark of biological intelligence. Although artificial agents extract reusable skills from past experience and recombine them in a hierarchical manner, whether the brain similarly composes a novel behavior is largely unknown. In the present study, I show that deep reinforcement learning agents learn to solve a novel composite task by additively combining representations of prelearned action values of constituent subtasks. Learning efficacy in the composite task was further augmented by the introduction of stochasticity in behavior during pretraining. These theoretical predictions were empirically tested in mice, where subtask pretraining enhanced learning of the composite task. Cortex-wide, two-photon calcium imaging revealed analogous neural representations of combined action values, with improved learning when the behavior variability was amplified. Together, these results suggest that the brain composes a novel behavior with a simple arithmetic operation of preacquired action-value representations with stochastic policies.
Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a
Authors: Gwennaëlle C. Monnot, Marcin Wegrecki, Tan-Yun Cheng, Yi-Ling Chen, Brigitte N. Sallee, Reka Chakravarthy, Ioanna Maria Karantza, Shin Yi Tin, Alexandra E. Khaleel, Isha Monga, Laura N. Uwakwe, Alice Tillman, Bin Cheng, Soundos Youssef, Soo Weei Ng, Adam Shahine, Javier A. Garcia-Vilas, Anne-Catrin Uhlemann, Lindsey A. Bordone, Arnold Han, Christine H. Rohde, Graham Ogg, D. Branch Moody, Jamie Rossjohn, Annemieke de Jong
Journal: Nature Immunology (2022)
Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds
Authors: Fatemeh S. Majedi, Mohammad Mahdi Hasani-Sadrabadi, Timothy J. Thauland, Sundeep G. Keswani, Song Li, Louis-S. Bouchard, Manish J. Butte
Journal: Nature Biomedical Engineering (2022)
WHO: Vaccine Market Report Highlights Inequitable Global Distribution
Authors: Howard Larkin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Prognostic value of translocation 11;14 in patients with relapsed/refractory myeloma receiving anti-CD38 therapy
Authors: Ghulam Rehman Mohyuddin, Rajshekhar Chakraborty, Gregory S. Calip, Mustafa S. Ascha, Xiaoliang Wang, Samuel M. Rubinstein, Sascha Tuchman, Luciano Costa, Benjamin Haaland, Smith Giri, Hira Mian, Rafael Fonseca, Douglas Sborov
Journal: Blood Cancer Journal (2022)
Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation–Sparing Approaches: An International Cohort Study
Authors: Craig Erker, Martin Mynarek, Simon Bailey, Claire M. Mazewski, Lorena Baroni, Maura Massimino, Juliette Hukin, Dolly Aguilera, Andrea M. Cappellano, Vijay Ramaswamy, Alvaro Lassaletta, Sébastien Perreault, Cassie N. Kline, Revathi Rajagopal, George Michaiel, Michal Zapotocky, Vicente Santa-Maria Lopez, Andres Morales La Madrid, Chantel Cacciotti, Eric S. Sandler, Lindsey M. Hoffman, Darren Klawinski, Sara Khan, Ralph Salloum, Anna L. Hoppmann, Valérie Larouche, Kathleen Dorris, Helen Toledano, Stephen W. Gilheeney, Mohamed S. Abdelbaki, Beverly Wilson, Derek S. Tsang, Jeffrey Knipstein, Michal Yalon Oren, Shafqat Shah, Jeffrey C. Murray, Kevin F. Ginn, Zhihong J. Wang, Gudrun Fleischhack, Denise Obrecht, Svenja Tonn, Virginia L. Harrod, Kara Matheson, Bruce Crooks, Douglas R. Strother, Kenneth J. Cohen, Jordan R. Hansford, Sabine Mueller, Ashley Margol, Amar Gajjar, Girish Dhall, Jonathan L. Finlay, Paul A. Northcott, Stefan Rutkowski, Steven C. Clifford, Giles Robinson, Eric Bouffet, Lucie Lafay-Cousin
Journal: Journal of Clinical Oncology (2022)

Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy.
Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia
Authors: Jérôme Bertherat, Isabelle Bourdeau, Lucas Bouys, Fanny Chasseloup, Peter Kamenický, André Lacroix
Journal: Endocrine Reviews (2022)

Abstract Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein–coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.
Where do we stand in AI for endoscopic image analysis? Deciphering gaps and future directions
Authors: Sharib Ali
Journal: npj Digital Medicine (2022)

Recent developments in deep learning have enabled data-driven algorithms that can reach human-level performance and beyond. The development and deployment of medical image analysis methods have several challenges, including data heterogeneity due to population diversity and different device manufacturers. In addition, more input from experts is required for a reliable method development process. While the exponential growth in clinical imaging data has enabled deep learning to flourish, data heterogeneity, multi-modality, and rare or inconspicuous disease cases still need to be explored. Endoscopy being highly operator-dependent with grim clinical outcomes in some disease cases, reliable and accurate automated system guidance can improve patient care. Most designed methods must be more generalisable to the unseen target data, patient population variability, and variable disease appearances. The paper reviews recent works on endoscopic image analysis with artificial intelligence (AI) and emphasises the current unmatched needs in this field. Finally, it outlines the future directions for clinically relevant complex AI solutions to improve patient outcomes.
Novel insights into Hodgkin lymphoma biology by single-cell analysis
Authors: Tomohiro Aoki, Christian Steidl
Journal: Blood (2022)

The emergence and rapid development of single-cell technologies mark a paradigm shift in cancer research. Various technology implementations represent powerful tools to understand cellular heterogeneity, identify minor cell populations that were previously hard to detect and define, and make inferences about cell-to-cell interactions at single-cell resolution. Applied to lymphoma, recent advances in single-cell RNA sequencing have broadened opportunities to delineate previously underappreciated heterogeneity of malignant cell differentiation states and presumed cell of origin, and to describe the composition and cellular subsets in the ecosystem of the tumor microenvironment (TME). Clinical deployment of an expanding armamentarium of immunotherapy options that rely on targets and immune cell interactions in the TME emphasizes the requirement for a deeper understanding of immune biology in lymphoma. In particular, classic Hodgkin lymphoma (CHL) can serve as a study paradigm because of its unique TME, featuring infrequent tumor cells among numerous nonmalignant immune cells with significant interpatient and intrapatient variability. Synergistic to advances in single-cell sequencing, multiplexed imaging techniques have added a new dimension to describing cellular cross talk in various lymphoma entities. Here, we comprehensively review recent progress using novel single-cell technologies with an emphasis on the TME biology of CHL as an application field. The described technologies, which are applicable to peripheral blood, fresh tissues, and formalin-fixed samples, hold the promise to accelerate biomarker discovery for novel immunotherapeutic approaches and to serve as future assay platforms for biomarker-informed treatment selection, including immunotherapies.
Optimised surveillance of minor to moderate bronchial dysplasia in a risky population: more precision strategies needed
Authors: Xiao Fei Wang, Qing Yun Li
Journal: European Respiratory Journal (2022)

<b>The utility of repeated bronchoscopy for surveillance of bronchial low-grade preinvasive lesions in high-risk patients is quite limited in SELEPREBB trial. More selected risky patients or combination with CT imaging could be a direction of further research.</b>https://bit.ly/3PsuJ7i
Region-selective control of the thalamic reticular nucleus via cortical layer 5 pyramidal cells
Authors: Nóra Hádinger, Emília Bősz, Boglárka Tóth, Gil Vantomme, Anita Lüthi, László Acsády
Journal: Nature Neuroscience (2022)

Corticothalamic pathways, responsible for the top-down control of the thalamus, have a canonical organization such that every cortical region sends output from both layer 6 (L6) and layer 5 (L5) to the thalamus. Here we demonstrate a qualitative, region-specific difference in the organization of mouse corticothalamic pathways. Specifically, L5 pyramidal cells of the frontal cortex, but not other cortical regions, establish monosynaptic connections with the inhibitory thalamic reticular nucleus (TRN). The frontal L5-TRN pathway parallels the L6-TRN projection but has distinct morphological and physiological features. The exact spike output of the L5-contacted TRN cells correlated with the level of cortical synchrony. Optogenetic perturbation of the L5-TRN connection disrupted the tight link between cortical and TRN activity. L5-driven TRN cells innervated thalamic nuclei involved in the control of frontal cortex activity. Our data show that frontal cortex functions require a highly specialized cortical control over intrathalamic inhibitory processes.
A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity
Authors: Natascha Roehlen, Antonio Saviano, Houssein El Saghire, Emilie Crouchet, Zeina Nehme, Fabio Del Zompo, Frank Jühling, Marine A. Oudot, Sarah C. Durand, François H. T. Duong, Sara Cherradi, Victor Gonzalez Motos, Nuno Almeida, Clara Ponsolles, Laura Heydmann, Tessa Ostyn, Antonin Lallement, Patrick Pessaux, Emanuele Felli, Andrea Cavalli, Jacopo Sgrignani, Christine Thumann, Olga Koutsopoulos, Bryan C. Fuchs, Yujin Hoshida, Maike Hofmann, Mogens Vyberg, Birgitte Martine Viuff, Elisabeth D. Galsgaard, Greg Elson, Alberto Toso, Markus Meyer, Roberto Iacone, Tamas Schweighoffer, Geoffrey Teixeira, Solange Moll, Claudio De Vito, Tania Roskams, Irwin Davidson, Danijela Heide, Mathias Heikenwälder, Mirjam B. Zeisel, Joachim Lupberger, Laurent Mailly, Catherine Schuster, Thomas F. Baumert
Journal: Science Translational Medicine (2022)

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.
Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell–Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial
Authors: Catherine Thieblemont, Tycel Phillips, Herve Ghesquieres, Chan Y. Cheah, Michael Roost Clausen, David Cunningham, Young Rok Do, Tatyana Feldman, Robin Gasiorowski, Wojciech Jurczak, Tae Min Kim, David John Lewis, Marjolein van der Poel, Michelle Limei Poon, Mariana Cota Stirner, Nurgul Kilavuz, Christopher Chiu, Menghui Chen, Mariana Sacchi, Brian Elliott, Tahamtan Ahmadi, Martin Hutchings, Pieternella J. Lugtenburg
Journal: Journal of Clinical Oncology (2022)

PURPOSE Epcoritamab is a subcutaneously administered CD3xCD20 T-cell–engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20 + B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037 ), adults with relapsed or refractory CD20 + large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20‐83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell–associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
Variants in <i>ALDH1A2</i> reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis
Authors: Linyi Zhu, Pragash Kamalathevan, Lada A. Koneva, Jadwiga Miotla Zarebska, Anastasios Chanalaris, Heba Ismail, Akira Wiberg, Michael Ng, Hayat Muhammad, John Walsby-Tickle, James S.O. McCullagh, Fiona E. Watt, Stephen N. Sansom, Dominic Furniss, Matthew D. Gardiner, Tonia L. Vincent
Journal: Science Translational Medicine (2022)

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2 , which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.
Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling
Authors: Nicholas R. Anderson, Vipul Sheth, Hui Li, Mason W. Harris, Shaowei Qiu, David K. Crossman, Harish Kumar, Puneet Agarwal, Takashi Nagasawa, Andrew J. Paterson, Robert S. Welner, Ravi Bhatia
Journal: Leukemia (2022)
Omicron BQ.1 and BQ.1.1 escape neutralisation by omicron subvariant breakthrough infection
Authors: Xiao-Lin Jiang, Ka-Li Zhu, Xue-Jun Wang, Guo-Lin Wang, Yi-Ke Li, Xue-Juan He, Wen-Kui Sun, Peng-Xiang Huang, Jin-Zhong Zhang, Hui-Xia Gao, Er-Hei Dai, Mai-Juan Ma
Journal: The Lancet Infectious Diseases (2022)